1. Field of the Invention
The invention relates to succinamide derivative matrix-metalloprotease inhibitors useful in treatment of disease in which matrix-metalloprotease promoted connective tissue remodelling is a causative factor, for example, rheumatoid arthritis and cancer, and to method of preparation and method of use thereof and methods of preparation of intermediates therefor.
2. Information Disclosure Statement
Davidson et al. (British Bio-technology Limited) PCT Application WO 90/05716 published May 31, 1990 describes collagenase inhibitors having the structural formula ##STR2## wherein R.sub.1 [sic] represents a hydrogen atom or a C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkenyl, phenyl, phenyl(C.sub.1 -C.sub.6)alkyl, C.sub.1 -C.sub.6 alkylthiomethyl, phenylthiomethyl, substituted phenylthiomethyl, phenyl(C.sub.1 -C.sub.6)alkylthiomethyl or heterocyclylthiomethyl group; or R.sup.1 represents --SR.sup.x wherein R.sup.x represents a group (.alpha.); ##STR3## R.sup.2 represents a hydrogen atom or a C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkenyl, phenyl(C.sub.1 -C.sub.6)alkyl, cycloalkyl(C.sub.1 -C.sub.6)alkyl, or cycloalkenyl(C.sub.1 -C.sub.6)alkyl; R.sup.3 represents an amino acid residue with R or S stereochemistry of a C.sub.1 -C.sub.6 alkyl, benzyl, (C.sub.1 -C.sub.6)alkoxybenzyl or benzyloxy(C.sub.1 -C.sub.6)alkyl group; R.sup.4 represents a hydrogen atom or a methyl group; n is an integer from 1 to 6; and A represents the group --NH.sub.2, a substituted acyclic amine or a heterocyclic base; or a salt and/or N-oxide and/or (where the compound is a thio-compound) a sulphoxide or sulphone thereof . . .
and the corresponding compounds having the structural formula ##STR4## useful as intermediates for preparing the compounds of formula (I).
Campion et al. (British Bio-technology Limited) PCT Application WO 91/02716 published Mar. 7, 1991 describes collagenase inhibitors having the structural formula ##STR5## wherein R.sup.1 represents a hydrogen atom or a C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkenyl, phenyl, phenyl(C.sub.1 -C.sub.6)alkyl, C.sub.1 -C.sub.6 alkylthiomethyl, phenylthiomethyl, substituted phenylthiomethyl, phenyl(C.sub.1 -C.sub.6)alkylthiomethyl or heterocyclylthiomethyl group; or R.sup.1 represents --S--R.sup.x wherein R.sup.x represents a group .alpha.; ##STR6## R.sup.2 represents a hydrogen atom or a C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkenyl, phenyl(C.sub.1 -C.sub.6)alkyl, cycloalkyl(C.sub.1 -C.sub.6)alkyl, or cycloalkenyl(C.sub.1 -C.sub.6)alkyl; R.sup.3 represents an amino acid side chain or a C.sub.1 -C.sub.6 alkyl, benzyl, (C.sub.1 -C.sub.6)alkoxybenzyl, benzyloxy(C.sub.1 -C.sub.6)alkyl or benzyloxybenzyl group; R.sup.4 represents a hydrogen atom or a methyl group; R.sup.5 represents a group (CH.sub.2).sub.n A; or R.sup.4 and R.sup.5 together represent a group .beta.; ##STR7## Q represents CH.sub.2 or CO; m is an integer from 1 to 3; n is an integer from 1 to 6; and A represents a hydroxy, (C.sub.1 -C.sub.6)alkoxy, (C.sub.2 -C.sub.7)acyloxy, (C.sub.1 -C.sub.6)alkylthio, phenylthio, (C.sub.2 -C.sub.7)acylamino or N-pyrrolidone group or a salt and/or N-oxide and/or (where the compound is a thio-compound) a sulphoxide or sulphone thereof . . .
and the corresponding compounds having the structural formula ##STR8## useful as intermediates for preparing the compounds of formula (I).